Numerous agents, such as diarrheogenic prostaglandins, various parasitic oranisms, and toxins produced by microbial agents, are known in the art to have a recognized diarrheogenic potential in mammals. One measure of the potential for the induction of diarrhea for a given agent is its ability to cause the accumulation of fluid in the small intestine of standard laboratory animals treated with or exposed to the agent. This phenomena of fluid accumulation, referred to as enteropooling, is quantitatively determined by methods known in the art. See, for example, Robert, A., et al., Prostaglandins, 11:809-828 (1976). Agents which can cause enteropooling at a level sufficient to cause diarrhea are referred to herein as enteropooling inducers.
One such class of enteropooling inducers, the diarrheogenic prostaglandins, are members of a family of naturally-occurring fatty acids (such as PGE.sub.2 and PGF.sub.2 .alpha.), and include various chemical analogs thereof known in the art. Among these prostaglandin analogs known in the art there are the PGC-type compounds of U.S. Pat. No. 3,993,686, the 9-deoxy-9-methylene-PGF-type compounds of U.S. Pat. Nos. 4,021,467 and 4,060,534; the 11-deoxy-PG-type compounds of U.S. Pat. Nos. 4,029,693 and 3,987,072; the 8.beta., 12.alpha.-PG-type compounds of U.S. Pat. No. 3,979,483; the 2,2-difluoro-PG-type compounds of U.S. Pat. Nos. 4,001,300; the cis-4,5-didehydro-PG-type compounds of U.S. Pat. Nos. 4,032,561 and 3,933,889; the inter-phenylene-PG-type compounds of U.S. Pat. Nos. 4,020,097 and 3,997,566; the 5,6-didehydro-PG.sub.2 -type or 4,4,5,5-tetradehydro-PG.sub.1 -type compounds of U.S. Pat. No. 4,013,695; the 5-oxa-PG.sub.1 -type compounds of U.S. Pat. Nos. 3,931,279 and 3,864,387; the 4-oxa-PG.sub.1 -type and 3-oxa-PG.sub.1 -type compounds of U.S. Pat. No. 3,944,593; the 13-cis-PG-type compounds of U.S. Pat. No. 4,026,909; the 13,14-didehydro-PG-type compounds of U.S. Pat. Nos. 4,029,681 and 4,018,803; the .omega.-aryl-PG-type compounds of U.S. Pat. No. 3,987,087; the .omega.-aryloxy-PG-type compounds of U.S. Pat. No. 3,864,387; the 16-alkyl-PG-type compounds of U.S. Pat. No. 3,903,131; the 16-fluoro-PG-type compounds of U.S. Pat. No. 3,962,293; the 15-methyl-PG-type compounds of U.S. Pat. No. 3,728,382.
While the naturally-occurring prostaglandins are carboxylic acids, numerous derivatives thereof are known in the art. For example, ester derivatives, including especially aromatic and phenacyl esters, are known in the art. See U.S. Pat. Nos. 3,069,032, 3,598,858, 3,979,440, and 3,984,062. Likewise, salts of these carboxylic acids are known in the art. See U.S. Pat. Nos. 3,069,332 and 3,958,858 cited above, as well as other references such as U.S. Pat. Nos. 3,657,327 and 3,888,916. Other derivatives of the prostaglandins, such as the amides thereof, are known in the art. See U.S. Pat. Nos. 3,853,941, 3,884,942, 3,903,299, 3,880,883, and 3,953,470.
Finally, there are also known macrocyclic lactone derivatives of the prostaglandins as is, for example, described by Corey, E. J., et al., JACS 97:653 (1975) and U.S. Pat. Nos. 3,931,206, 4,067,991, 4,049,648, 4,032,543, 4,045,449, and 4,049,678.
In addition to these various carbonyl-containing prostaglandin analogs, there are likewise known in the art acidic, non-carboxylic prostaglandin analogs such as tetrazoles and sulfonates. See for example the 2-decarboxycarboxy-2-tetrazolyl-PG analogs described in U.S. Pat. Nos. 3,883,513, 3,932,389, 3,984,400, and 4,035,360. Also 2-decarboxy-2-sulfonyl-type compounds are described in U.S. Pat. No. 3,922,301.
Among the various other modifications at the C-2 position of the known prostaglandin analogs is the replacement of the carboxyl with an amine, as is for example described in U.S. Pat. No. 4,073,808 and Derwent Farmdoc CPI No. 46957V (abstracting Belgian Pat. No. 849,963).
Numerous references also describe primary alcohols corresponding to the known prostaglandins and analogs thereof as are described in U.S. Pat. Nos. 4,028,419, 4,055,602, 4,032,576, 3,931,207, 3,878,239, 3,966,792, 4,024,174, 3,962,312, 3,636,120, 3,723,528, 3,895,058, 3,954,881, 4,004,021, and 3,962,218. In addition to these 2-decarboxy-2-hydroxymethyl-PG compounds, there are known the corresponding C-2 aldehydes as described in U.S. Pat. Nos. 3,931,296 and 3,953,435. See also Derwent Farmdoc CPI No. 35953X and at 93049X for a description of further 2-decarboxy-2-carboxaldehyde-PG analogs. Finally, the C-2 acetals thereof are described at Derwent Farmdoc CPI No. 94924X.
There are further known in the art 11-oxo-prostaglandins, notably PGD-type, 9.beta.-PGD-type, 9-deoxy-PGD-type, 9-deoxy-9,10-didehydro-PGD-type, and the corresponding 12,13-didehydro analogs thereof. These 11-oxo-prostaglandins are described in U.S. Pat. No. 4,016,184.
In addition to the various prostaglandins, including prostaglandin analogs and 11-oxo-prostaglandins known to the art, there are further known the prostacyclins. As that term is used herein, the term prostacyclins refers not only to prostacyclin or PGI.sub.2 itself, but various, and notably more stable, analogs thereof.
Prostacyclin is an unsaturated heterocyclic carboxylic acid and its preparation and certain of its pharmacological uses are described in Belgian Pat. No. 851,122 (published as Derwent Farmdoc CPI No. 57511Y) and Belgian Pat. No. 854,463 (published as Derwent Farmdoc CPI No. 81213Y). Among the analogs of prostacyclin are the 5,6-dihydro-PGI.sub.1 compounds, described in Belgian Pat. No. 855,224 (published as Derwent Farmdoc CPI No. 86540Y); the 9-thia analog of prostacyclin, described at JACS 99:7734 (1977); the 4,5-didehydro-PGI.sub.1 compounds, described at JCS Chem. Comm. 1977:331-332 and JACS 99:2006-2008 (1977) and U.S. Pat. No. 4,109,082, filed on an even date herewith; the C-9 nitrogen analogs of prostacyclin, described in U.S. Pat. No. 4,097,489; the 5-hydroxy-PGI.sub.1 compounds, described in U.S. Pat. No. 4,110,532 the 4-oxo-PGI.sub.1 compounds, described in U.S. Pat. No. 4,126,744 the 7,8-didehydro-PGI.sub.1 compounds, described in U.S. Pat. No. 4,151,351, the 6,7-didehydro-PGI.sub. 1 compounds, described in U.S. Pat. No. 4,128,713 the carbocyclic analogs of prostacyclin, described in German Offenlegungschrift 2,329,092, the C-5 isomers of prostacyclin, described in U.S. Pat. No. 4,150,222, the 9-deoxy-9-epoxymethylene-PGI.sub.1 compounds, described in U.S. Pat. No. 4,130,569, and the 7a-homo-PGI.sub.1 compounds, described in U.S. Ser. No. 260,518, now abandoned.